Progress in Understanding and Treating SCN2A-Mediated Disorders

Abstract

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel Na_V1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders.

Keywords: Na(V)1.2; autism spectrum disorder; developmental delay; epilepsy; intellectual disability; neurodevelopment; neurodevelopmental disorder; sodium channel.

Figure 1. Overview of SCN2A/Na_V1.2

A) Na_V1.2 resides in the cell membrane and is a pseudo-heterotetramer composed of four domains, called I-IV. Each domain contains a voltage sensor (cyan) and a pore loop with a ring of amino acids (DEKA) making up the ion selectivity filter (pink). The cytoplasmic loop between domains III and IV is the fast inactivation gate (dark blue, see D). Two isoforms are known, differing by one amino acid at p.209 (orange) [2]. The channel binds to Ankyrin G (ANK3), which anchors it to the membrane (green) [79], and interacts with calmodulin, which likely has a regulatory role (purple) [80]. Stop codons before the nonsense mediated decay boundary (red) are predicted to prevent protein translation, while those after this boundary may not. B) Na_v1.2 homology model of the transmembrane region, top view. Each domain is labeled. For domain I, transmembrane segments 1–6 are labeled S1–S6. S1–S4v represents the voltage sensing domain (VSD). The voltage sensor is labeled S4v and is colored cyan. S5–S6 represents the pore forming domain (PFD). The Cα carbons from each residue in the DEKA motif are represented as pink spheres. The Cα carbon of the residue that differs between the neonatal and adult isoforms is represented as a yellow sphere. The selectivity filter is represented by an asterisk. Model [81] is based on the Na_V1.7 chimeric crystallographic structure [61]. C) Na_v1.2 homology model of the transmembrane region, side view. Purple spheres represent sodium passing through the selectivity filter of Na_V1.2. D) Na_V1.2 is closed at resting potential. Depolarization opens the channel, allowing sodium flux, after which the channel is blocked by the fast inactivation gate (blue). As the membrane voltage returns to rest the channel resets through hyperpolarization. E) Location of missense variants observed in individuals with infantile epileptic encephalopathy and benign (familial) infantile seizures (red) and autism spectrum disorder/intellectual disability (blue). Increased color intensity represents multiple variants in proximity. Panels A and E are based on previously published illustrations [26].

Figure 2. Current model of SCN2A pathophysiology

Gain of function (GoF) variants (left) potentiate glutamatergic neuronal excitability, leading to infantile-onset seizure phenotypes, whereas loss of function (LoF) variants (right) impair excitability, leading to ASD and/or intellectual disability [24]. Seizure severity is correlated with the degree of GoF, with variants that cause the most excitability leading to infantile epileptic encephalopathy (IEE), while milder variants lead to benign (familial) infantile seizures (BIS) that resolve around 1–2 years of age without apparent neurological sequelae. The threshold that distinguishes IEE and BIS variants may be related to the degree of compensation of neuronal excitability by Na_V1.6, which replaces Na_V1.2 in generating action potentials and has a lower threshold for activation than wild type Na_V1.2.

Figure 3. Homology of SCN2A across model organisms and voltage-gated sodium channels

A) Voltage-gated sodium channels (Na_V) are derived from T-type voltage-gated calcium channels (Ca_V3) [42,43]. In fruit flies the ancestral Na_V2 channel, with the ion selectivity filter composed of the four amino acids DEEA, co-exists with the Na_V1 channel with the DEKA filter. All Na_V channels in humans are derived from this Na_V1 DEKA filter, while the Na_V2 filter has been lost [45,46]. A series of gene duplication and differentiation events give rise to the ten channels seen in humans and reflected in the proximity of similar channels in the genome [45,46]. B) Homology between the 10 Na_V channels in humans. A more intense shade of blue indicates higher homology. *Zebrafish have two copies of each of these four Na_V channels due to relatively recent genome duplication. CNS: Central nervous system; PNS: Peripheral nervous system; GTEx: Genotype-Tissue Expression Project (www.gtexportal.org).